title: Systematic study of non-natural short cationic lipopeptides as novel broad-spectrum antimicrobial agents.
abstract: We describe the design and synthesis of a new series of non-natural short cationic lipopeptides (MW = 700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as Gram-positive, Gram-negative bacteria, fungi including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP16 possesses broad-spectrum antimicrobial activity and has MICs in the range of 1.5-6.25 μg/mL against Escherichia coli, S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, and MRSE. All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells (HC50 > 250 μg/mL). Moreover, most potent lipopeptides (LP16 and LP23) did not induce drug resistance in S. aureus even after 15 rounds of passaging. In addition, a representative lipopeptide (LP16) showed tryptic stability for 24 h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics.
authors.affiliation: Department of Pharmacy, Jaypee University of Information Technology, Solan, 173234, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Lohan
authors.forename: Swaranjit S
authors.initials: SS
authors.lastname: Cameotra
authors.forename: Gopal S
authors.initials: GS
authors.lastname: Bisht
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests
chemical_list: D000890:Anti-Infective Agents; D055666:Lipopeptides
keywords: antibiotic resistance; antimicrobial peptides; hemolytic activity; lipopeptides